This is competitive renewal of grant R01-AR32599, aimed at identifying the etiology of Brazilian pemphigus foliaceus or Foqo Selvagem (fs). FS is a human autoimmune disease mediated by pathogenic autoantibodies directed against desmoglein 1 (dsg1). Sensitized individuals living in certain rural areas of Brazil produce these autoantibodies. We have identified a new FS focus, with a 3% of disease-prevalence, and a unique set of environmental, genetic, and cultural characteristics. This community, the Limao Verde Reservation located in central Brazil, is composed of approximately 1100 members of the Terena Indian tribe. Geographic, familial, HLA and temporal clustering patterns have been described among the 35 cases of FS seen in this reservation. Based on our studies we predict that normal controls (pre-clinical state of FS), when exposed to certain environmental antigen(s), produce an early lgG1 anti-dsg1 response; only later, and in certain predisposed individuals, does this response become pathogenic and is mediated by lgG4 anti-dsg1 antibodies (clinical state of ES). Encouraging preliminary studies suggest that saliva from blood-feeding insects, such as kissing bugs and sand flies, may be the source of cross-reactive antigens that trigger anti-dsg1 autoantibody responses. Aims 1 and 2 include epidemiological studies designed to further define genetic and environmental risk factors associated with FS. Cohorts composed of adults and younger individuals will be followed using clinical, serological and ecological data. Serological evidence of anti-dsg1 IgG, lgG1 and lgG4 responses will be serially evaluated. The 29 FS patients that are alive will be followed, assessing the therapy as well as the environmental factors that may be linked to relapses. Aim 3 will focus on assessing the serological responses of patients with Chagas (kissing bugs) and Leishmaniasis (sand flies) to dsg1 and molecularly characterizing the salivary antigens of these blood-feeding insects. Aim 4 will test the response of FS T cells to the putative salivary antigens and Aim 5 will include studies on the frequency of FS-like disease in domestic animals. The possible existence of an "endemic pemphigus vulgaris" variant in Brazil and the evaluation of the sand fly and kissing bug species in Limao Verde are also included in this latter aim. It is likely that characteristics of the mechanism of autoimmunity for FS will be shared with other human autoimmune diseases and what we learn from ES will be applicable to the study of human autoimmunity.